Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalized dengue cases in 9–45 years old individuals, there were 971 deaths. Risk of dying was 11 times higher in the presence of underlying common comorbidities (renal, infectious, pulmonary disease and diabetes), similar to the risk of dying from severe dengue and much higher with the combination. Ensuring access to integrated dengue preventative measures in individuals ≥9 years including those with comorbidities may help achieve the WHO objective of 50% reduction in mortality, 25% reduction in morbidity to dengue by 2020.